Newly diagnosed type 1 diabetes mellitus in a human immunodeficiency virus-infected patient with antiretroviral therapy-induced immune reconstitution inflammatory syndrome: a case report.

BACKGROUND: Diabetes that develops in human immunodeficiency virus (HIV)-infected patients who receive antiretroviral therapy (ART) is usually type 2 diabetes mellitus (T2DM); however, autoimmune diabetes, such as type 1 diabetes mellitus (T1DM) can also develop in this population. After treatment with ART, patients might experience clinical deterioration following an increase in the CD4 cell count, which is termed immune reconstitution inflammatory syndrome (IRIS). Here, we describe an HIV-infected patient on ART who developed T1DMat due to IRIS, highlighting the clinical complexity in diagnosis and treatment. CASE PRESENTATION: A 36-year-old man infected with HIV had a nadir CD4 cell count of 15.53/µL before medication, which increased to 429.09/µL after 9 months of regular ART. The fasting serum glucose at 9 months was between 96 mg/dL and 117 mg/dL. After 11 months of ART, the patient was admitted to hospital for diabetic ketoacidosis (DKA) and Graves' disease (GD). Noninsulin antidiabetics (NIADs) were prescribed following the resolution of DKA. However, poor glycemic control was noted despite well-titrated NIADs. Further investigation demonstrated poor pancreatic beta cell function and elevated anti-glutamic acid decarboxylase (anti-GAD) and anti-tyrosine phosphatase-like insulinoma antigen 2 (anti-IA2) titers. According to the results, he was diagnosed with T1DM and received multiple daily injections(MDI) of insulin. The regimen of MDI was insulin degludec as basal insulin and insulin aspart as prandial insulin. After MDI therapy, his glycemic control was improved. CONCLUSION: In this case, T1DM was ascribed to IRIS. Although this phenomenon has been demonstrated in previous case reports, further study is necessary to realize the mechanism of this association. Therefore, we emphasize that when HIV-infected patients on ART experience an unstable blood glucose level and abnormal thyroid function, physicians should consider T1DM and GD associated with ART-induced IRIS to reduce the subsequent complications and more serious endocrine dysfunction.

Effect of metformin monotherapy and dual or triple concomitant therapy with metformin on glycemic control and lipid profile management of patients with type 2 diabetes mellitus.

Background: In this study, we aimed to compare the effects of metformin-based dual therapy versus triple therapy on glycemic control and lipid profile changes in Taiwanese patients with type 2 diabetes mellitus (T2DM). Methods: In total, 60 patients were eligible for participation in this study. Patients received at least 24 months of metformin monotherapy, dual therapy, or triple therapy with metformin plus linagliptin (a dipeptidyl peptidase 4 (DPP-4) inhibitor) or dapagliflozin (a sodium-glucose cotransporter-2 (SGLT2) inhibitor). Blood samples were collected from each patient, followed by evaluation of changes in their blood glucose control and lipid profile-related markers. Results: A combination of metformin and DPP4 and SGLT2 inhibitor therapy more effectively reduced low-density lipoprotein cholesterol (LDL-C) (p = 0.016) than metformin monotherapy. A combination of metformin and DPP4 and SGLT2 inhibitor therapy more effectively improved total cholesterol (Chol, p = 0.049) and high-density lipoprotein cholesterol (HDL-C) than metformin monotherapy (p = 0.037). Metformin plus linagliptin dual therapy was more effective than metformin monotherapy in reducing glycosylated hemoglobin (HbA1C, p = 0.011). Patients who received a combination of linagliptin and empagliflozin showed a significant reduction in their fasting blood glucose (p = 0.019), HbA1c (p = 0.036), and Chol (p = 0.010) compared with those who received linagliptin dual therapy. Furthermore, patients who received metformin plus dapagliflozin and saxagliptin showed significantly reduced Chol (p = 0.011) and LDL-C (p = 0.035) levels compared with those who received metformin plus dapagliflozin. Conclusion: In conclusion, dual therapy with metformin and linagliptin yields similar glycemic control ability to triple therapy. Among metformin combination triple therapy, triple therapy of empagliflozin and linagliptin might have a better glycemic control ability than dual therapy of linagliptin. Moreover, Triple therapy of dapagliflozin and saxagliptin might have a better lipid control ability than dual therapy of dapagliflozin.

Crystal structure of the α-ketoglutarate-dependent non-heme iron oxygenase CmnC in capreomycin biosynthesis and its engineering to catalyze hydroxylation of the substrate enantiomer.

CmnC is an α-ketoglutarate (α-KG)-dependent non-heme iron oxygenase involved in the formation of the l-capreomycidine (l-Cap) moiety in capreomycin (CMN) biosynthesis. CmnC and its homologues, VioC in viomycin (VIO) biosynthesis and OrfP in streptothricin (STT) biosynthesis, catalyze hydroxylation of l-Arg to form ß-hydroxy l-Arg (CmnC and VioC) or ß,γ-dihydroxy l-Arg (OrfP). In this study, a combination of biochemical characterization and structural determination was performed to understand the substrate binding environment and substrate specificity of CmnC. Interestingly, despite having a high conservation of the substrate binding environment among CmnC, VioC, and OrfP, only OrfP can hydroxylate the substrate enantiomer d-Arg. Superposition of the structures of CmnC, VioC, and OrfP revealed a similar folds and overall structures. The active site residues of CmnC, VioC, and OrfP are almost conserved; however Leu136, Ser138, and Asp249 around the substrate binding pocket in CmnC are replaced by Gln, Gly, and Tyr in OrfP, respectively. These residues may play important roles for the substrate binding. The mutagenesis analysis revealed that the triple mutant CmnCL136Q,S138G,D249Y switches the substrate stereoselectivity from l-Arg to d-Arg with ∼6% relative activity. The crystal structure of CmnCL136Q,S138G,D249Y in complex with d-Arg revealed that the substrate loses partial interactions and adopts a different orientation in the binding site. This study provides insights into the enzyme engineering to α-KG non-heme iron oxygenases for adjustment to the substrate stereoselectivity and development of biocatalysts.

Clinical significance of hepatic function in Graves disease with type 2 diabetic mellitus: A single-center retrospective cross-sectional study in Taiwan.

Graves disease (GD) and type 2 diabetes mellitus (T2DM) both impair liver function; we therefore explored the possibility of a relationship among diabetic control, thyroid function, and liver function. This retrospective, cross-sectional study compared serum liver function biomarkers of primary GD patients in a single center between 2016 and 2020, derived from clinical databases, and clarified the correlation of liver function in GD patients with or without T2DM. Furthermore, the diabetes mellitus group was divided into glycated hemoglobin A1C (HbA1C) <6.5% group and ≥6.5% group to further analyze the effect by disease control in patients. Statistical differences between groups were assessed using independent t tests to clarify the association of serum biomarkers between GD with T2DM. Pearson test was applied to assess within-group statistical correlation of serum biomarkers. The correlation of factors in each group was demonstrated by using the Kendall tau-b method and stepwise regression analysis. A total of 77 patients were included in the study. In the study population, glutamate pyruvate transaminase (GPT) was significantly correlated with thyroid-stimulating hormone, and HbA1C was significantly correlated with alkaline phosphatase (ALK-P), glutamate oxaloacetate transaminase (GOT), and GPT. An examination of GOT, GPT, free thyroxine (FT4), and HbA1C levels revealed a significant difference between the non-T2DM and T2DM groups. GPT also exhibited a significant correlation with triiodothyronine in the T2DM group. The T2DM group was further divided into groups: HbA1C <6.5% and ≥6.5%. The results demonstrated that ALK-P, GOT, GPT, and FT4 levels were significantly different between the groups. A significant correlation between ALK-P and thyroid-stimulating hormone and between GOT and FT4 was also identified in the HbA1C <6.5% group. Our single-center study revealed that diabetes affects liver function in patients with GD. For patients with T2DM, when liver function becomes impaired, thyroid function control deteriorates. GPT was correlated with triiodothyronine but not with FT4, which indicated the impairment of deiodination in the liver. This phenomenon was not observed in the non-T2DM population. The early detection of abnormal liver function in patients with GD and T2DM may help limit the development of comorbidities and improve disease management.

Is the level of serum lactate dehydrogenase a potential biomarker for glucose monitoring with type 2 diabetes mellitus?

Introduction: Type 2 diabetes mellitus (T2DM) is a metabolic disorder due to defects in insulin secretion or insulin resistance leading to the dysfunction and damage of various organs. To improve the clinical evaluation of short-term blood glycemic variability monitoring, it is critical to identify another blood cell status and nutritional status biomarker that is less susceptible to interference. This study identifies the significance of serum lactate dehydrogenase (LDH) level among T2DM patients treated in outpatient clinics and investigates the relationship of LDH level with other variables. Methods: This study comprised 72 outpatients with T2DM over 20 years of age. Blood samples were collected followed by a hematological analysis of serum glycated albumin (GA), LDH, fasting blood glucose, glycosylated hemoglobin, C-peptide, and insulin antibodies (insulin Ab). Results: Serum LDH level was significantly correlated with GA (p < 0.001), C-peptide (p = 0.04), insulin Ab (p = 0.03), and thyroid-stimulating hormone (TSH) levels (p = 0.04). Hence, we performed a linear regression analysis of hematological markers. GA (p < 0.001, r2 = 0.45) and insulin Ab (p < 0.001, r2 = 0.40) were significantly associated with LDH level. Then, we classified patients into low (<200 U/L) and high (≥200 U/L) serum LDH level groups, respectively. GA (p < 0.001), C-peptide (p = 0.001), and TSH (p = 0.03) showed significant differences in patients with high LDH levels compared with those in patients with low LDH levels. Conclusion: In conclusion, we suggested that LDH level was independent of long-term but associated with short-term blood glucose monitoring. The results indicated that changes in serum GA induced cell damage and the abnormal elevation of the serum level of LDH may occur simultaneously with glycemic variability. It has been reported that many biomarkers are being used to observe glucose variability in T2DM. However, LDH could provide a more convenient and faster evaluation of glycemic variability in T2DM.

Preventive Effect and Mechanism of Crossostephium chinense Extract on Balloon Angioplasty-Induced Neointimal Hyperplasia.

Balloon angioplasty-induced neointimal hyperplasia remains a clinical problem that must be resolved. The bioactivities of the Crossostephium chinense extract (CCE) have demonstrated potential in preventing the progression of restenosis. The present study evaluated whether CCE can suppress balloon angioplasty-induced neointima formation and elucidated its possible pharmacological mechanisms. A rat model of carotid arterial balloon angioplasty was established to evaluate the inhibitory effect of CCEs on neointimal hyperplasia. Two cell lines, A10 vascular smooth muscle cells (VSMCs) and RAW264.7 macrophages, were used to investigate the potential regulatory activities and pharmacological mechanisms of CCEs in cell proliferation and migration and in inflammation. Our in vitro results indicated that CCE3, the ethanolic extract of C. chinense, exerted the strongest growth inhibitory and antimigratory effects on VSMCs. CCE3 blocked the activation of focal adhesion kinase, platelet-derived growth factor receptor-ß (PDGFRB), and its downstream molecules (AKT and mTOR) and reduced the expression of matrix metalloproteinase-2. In addition, our findings revealed that CCE3 significantly increased the expression of miRNA-132, an inhibitory regulator of inflammation and restenosis, and suppressed the expression of inflammation-related molecules (inducible nitric oxide synthase, cyclooxygenase-2, interleukin- (IL-) 1ß, and IL-6). Our in vivo study results indicated that balloon injury-induced neointimal hyperplasia was inhibited by CCE3. CCE3 could reduce neointima formation in balloon-injured arteries, and this effect may be partially attributed to the CCE3-induced suppression of PDGFRB-mediated downstream pathways and inflammation-related molecules.

Formation of Stable Tin Perovskites Co-crystallized with Three Halides for Carbon-Based Mesoscopic Lead-Free Perovskite Solar Cells.

We synthesized and characterized methylammonium (MA) mixed tri-halide tin perovskites (MASnIBr2-x Clx ) for carbon-based mesoscopic solar cells free of lead and hole-transporting layers. Varied SnCl2 /SnBr2 ratios yielded tin perovskites with three halides (I, Br, and Cl) co-crystallized inside the tin-perovskite. When the SnCl2 proportion was ≥50 % (x≥1), phase separation occurred to give MASnI3-y Bry and MASnCl3-z Brz in the stoichiometric proportions of their precursors, confirmed by XRD. A device with MASnIBr1.8 Cl0.2 (SnCl2 =10 %) showed the best photovoltaic performance: JSC =14.0 mA cm-2 , VOC =380 mV, FF=0.573, and PCE=3.1 %, and long-term stability. Electrochemical impedance spectra (EIS) show superior charge recombination and dielectric relaxation properties for the MASnIBr1.8 Cl0.2 cell. Transient PL decays showed the intrinsic problem of tin-based perovskites with average lifetimes less than 100 ps.

Ovatodiolide suppresses allergic airway inflammation and hyperresponsiveness in a murine model of asthma.

Asthma, a complex pulmonary allergic disease, major therapy is applied of drugs to control the disease, but quickly recur after the drugs are stopped. In patients with severe asthma may show steroid resistance and would benefit from the development of novel therapeutic drugs. Ovatodiolide, a unique macrocyclic diterpenoid isolated from Anisomeles indica, showed therapeutic potential for the treatment of allergic asthma. As a model of allergic inflammation, we used ovalbumin (OVA)-immunized mice, which displayed T helper cell type 2 (TH2) cytokine expression in bronchoalveolar lavage fluid (BALF), as well as airway inflammation and hyperresponsiveness (AHR). The results showed that ovatodiolide suppressed TH2 activation, including cell proliferation and production of the TH2 related cytokines, interleukin (IL)-4, IL-5, IL-13, IL-33, eosinophil chemotactic protein (eotaxin), and also reduced airway hyperresponsiveness. In this study, ovatodiolide inhibited allergic asthma through downregulation of TH2 responses in a murine model of asthma.

The Concomitant Association of Thyroid Disorders and Myasthenia Gravis.

BACKGROUND: Some of the thyroid disorders (TD) and Myasthenia gravis (MG) are autoimmune related disease. The purpose of the study to evaluate the relationship of MG with all morphological and functional thyroid disorders. METHODS: We constructed a population-based cohort study during the period from January 2000-December 2002 by using reimbursement data from the Bureau National Health Insurance (NHI) system in Taiwan. Patients with TD and MG were identified by referring to the ICD-9-CM codes. (ICD-10-CM as reference) .The association of TD with MG occurred only in the same person within the study period. The Q value was used to measure the strength of disease-disease associations. RESULTS: We obtained 520628 TD and 7965 MG records for analysis. Diffuse toxic goiter had highest association rate, followed by nontoxic nodular goiter, simple goiter, chronic lymphocytic thyroiditis, thyroid cancer, and toxic nodular goiter. Female and older patients had a higher rate than their male and younger counterparts, respectively. Functional abnormalities revealed higher incidence of thyrotoxicosis and hypothyroidism in both sexes. We also found the strongest association in men with chronic thyroiditis, diffuse toxic goiter, thyrotoxicosis, acquired hypothyroidism, thyroid cancer, and simple goiter. While an intermediate association was observed in female with diffuse toxic goiter, in a male with toxic and nontoxic nodular/multinodular goiters, in female with thyrotoxicosis, thyroid cancer and acquired hypothyroidism. CONCLUSION: This population based cohort study showed potential association of all types of TD with MG, and observed a higher association rate in female autoimmune TD whereas males showed a higher strength of association.

Methods for detection and characterization of protein S-nitrosylation.

Reversible protein S-nitrosylation, defined as the covalent addition of a nitroso moiety to the reactive thiol group on a cysteine residue, has received increasing recognition as a critical post-translational modification that exerts ubiquitous influence in a wide range of cellular pathways and physiological processes. Due to the lability of the S-NO bond, which is a dynamic modification, and the low abundance of endogenously S-nitrosylated proteins in vivo, unambiguous identification of S-nitrosylated proteins and S-nitrosylation sites remains methodologically challenging. In this review, we summarize recent advancements and the use of state-of-art approaches for the enrichment, systematic identification and quantitation of S-nitrosylation protein targets and their modification sites at the S-nitrosoproteome scale. These advancements have facilitated the global identification of >3000 S-nitrosylated proteins that are associated with wide range of human diseases. These strategies hold promise to site-specifically unravel potential molecular targets and to change S-nitrosylation-based pathophysiology, which may further the understanding of the potential role of S-nitrosylation in diseases.

Trends in death rate from diabetes according to multiple-cause-of-death differed from that according to underlying-cause-of-death in Taiwan but not in the United States, 1987-2007.

OBJECTIVE: To examine whether trends in death rate from diabetes according to multiple-cause-of-death (MCOD) data differed from those according to underlying-cause-of-death (UCOD) data in Taiwan and the United States. STUDY DESIGN AND SETTING: We used multiple cause mortality files for the years 1987, 1992, 1997, 2002, and 2007 to calculate the age-adjusted death rates from diabetes according to MCOD and UCOD and the ratio between diabetes mortality according to UCOD and that according to MCOD (U/M ratio) in Taiwan and the United States. RESULTS: In Taiwan, diabetes mortality according to MCOD increased persistently from 1987 to 2007, but no prominent changes were found according to UCOD in men. For women, the death rates according to MCOD did not change significantly between 1987 and 2007 but decreased drastically from 1992 to 2007 according to UCOD. In the United States, the patterns of change in diabetes mortality according to MCOD were similar to those according to UCOD in both sexes. The U/M ratio of diabetes mortality declined persistently between 1987 and 2007 in Taiwan, but no prominent change was found in the United States. CONCLUSION: Trends in death rate from diabetes according to MCOD differed from that according to UCOD in Taiwan but not in the United States. To properly interpret cause-specific mortality trends, it is important to provide both MCOD and UCOD data.

Non-leisure time physical activity is an independent predictor of longevity for a Taiwanese elderly population: an eight-year follow-up study.

BACKGROUND: The aim of this study is to determine the relationship between leisure time physical activity (LTPA) and non-leisure time physical activity (NLTPA) on mortality among the elderly in Taiwan. METHODS: This is a prospective observational cohort study. We analyzed the mortality data from a cohort of 876 non-institutionalized community-dwelling men and women aged 65 years or over, who were recruited by stratified clustering random sampling from Tainan city and participated in the 1996 Elderly Medication Survey. Information about activities and other variables were collected by structured interviews at baseline in the participants' home. The Cox proportional hazards model and crude death rate were applied to estimate mortality risk. RESULTS: Among the 876 participants, 312 died during the follow-up period (1996-2004). In the unadjusted Cox regression model, subjects aged over 75, having difficulty in carrying out activities of daily living (ADLs), a BMI less than 18.5, a history of diabetes mellitus or stroke, without LTPA or being inactive in NLTPA, were found to have a higher risk of eight-year mortality. With the adjustment for age, gender, education level, habitual smoking and drinking, living status, BMI and medical history, the mortality was found to be higher among the sedentary subjects, either defined by lack of LTPA or NLTPA, with the hazard ratio of 1.27 (95% confidence interval [CI] = 0.97-1.66) and 1.45 (95% CI = 1.07-1.97), respectively. Furthermore, when both LTPA and NLTPA were put into the model simultaneously, NLTPA (HR = 1.40; 95% CI = 1.03-1.91) but not LTPA (HR = 1.21, 95% CI = 0.92-1.59) significantly predicted mortality during eight-year follow-up. In addition, subjects who were actively engaged in NLTPA had a lower mortality risk especially in subjects without performing LTPA. CONCLUSIONS: NLTPA is an independent predictor of longevity among older people in Taiwan. A physically active lifestyle, especially engaged in NLTPA, is associated with lower mortality risk in the elderly population. We thus suggest that encouraging older people to keep on engaging in customary NLTPA is good for their health.